Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to a method for the
preparation of a pharmaceutical composition for treating
peripheral orthostatic hypotension.
Orthostatic hypotension is caused by various diseases
and is classified as follows:
"Central" type
Shy-Drager syndrome
intracranial tumor
Parkinsonism
"Peripheral" type
diabetes mellitus
angitis
alcoholism
amyloidosis
acute pan-dysautonomia
familial dysautonomia (Riely-Day syndrome
syphilis
drug-induced orthostatic hypotension
idiopathic orthostatic hypotension
There is so far no single drug that proves effective
in the treatment of all forms of orthostatic hypotension.
Recently, it has been reported that tyramine combined with
a monoamine oxidase inhibitor is effective in the treat-
ment of "central" type orthostatic hypotension. However,
no reliable and effective drug for the treatment of
"peripheral" type orthostatic hypotension, in which the
deficit appears to be in the sympathetic nerves, has yet
been found.
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While studying the pathophysiology of familial amyloid
poly-neuropathy (FAP) as a model of "dysautonomia
syndrome", the present inventors found that DL- or L-threo-
3,4-dihydroxyphenylserine (threo-DOPS) is effective in
treating orthostatic hypotension, inducing substantial and
sustained elevation of blood pressure. The application of
DL-threo-DOPS to various kinds of orthostatic hypotension
proved that threo-DOPS is a novel drug for treating
"peripheral" type orthostatic hypotension.
It is already known that L-threo-DOPS is converted to
(-) norepinephrine by aromatic L-amino acid decarboxylase
in the living body. On the other hand, it is also known
that norepinephrine is one of the catecholamines and is
useful as a hypertensor. Therefore, it may generally be
expected that DOPS would have properties suitable as a
hypertensor. However, the effect of DOPS in the human
body can not necessarily be predicted since, contrary to
the above, DOPS has been reported as a compound having
anti-hypertensive action in certain cases e.g. Japanese
Patent Publication (unexamined) No. 49252/1975.
The pharmacological tests described hereinafter,
revealed that threo-DOPS has a selective effect on
"peripheral" orthostatic hypotension, while it does not
have a significant effect on the blood pressure of normal
subjects and of patients suffering from "central"
orthostatic hypotension.
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One object of the present invention is to provide a
novel pharmaceutical composition for treating "peripheral"
orthostatic hypotension.
Another object of the present invention is to provide
a method for preparation of a pharmaceutical composition
for treating "peripheral" orthostatic hypotension.
According to one aspect of the invention there is pro-
vided a pharmaceutical composition for treating peripheral
orthostatic hypotension, which comprises as the active
ingredient DL- or L-threo-3,4-dihydroxyphenylserine, or
a pharmaceutically acceptable acid addition salt thereof,
and a pharmaceutically acceptable carrier or diluent.
According to another aspect of the invention there is
provided a method for the preparation of a pharmaceutical
composition for treating peripheral orthostatic hypo-
tension, which comprises admixing DL- or L-threo-3,4-
dihydroxy-phenylserine, or a pharmaceutically acceptable
acid addition salt thereof, with a pharmaceutically
acceptable carrier or diluent.
Preferred embodiments of the present invention will
become apparent to those skilled in the art from the
following description with reference to the accompanying
drawings, in which:
Figure 1 shows the results obtained by intravenous
drip infusion of DL-threo-DOPS as is explained hereinafter;
Figure 2 shows the results obtained by oral adminis-
tration of DL-threo-DOPS to FAP patients;
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Figure 3 shows the results obtained by orally adminis-
tering DL-threo-DOPS to a FAP patient for 4 weeks; and
Figures 4 to 8 illustrate the results obtained by
intravenous drip infusion of DL-threo-DOPS into patients
suffering from familial diabetes mellitus, aortitis
syndrome, idiopathic orthostatic hypotension, acute pan-
dysautonomia, and ectopic pineal tumor, respectively.
In general, threo-DOPS exists as optical isomers
and there are L- and D-isomers as well as the racemic
DL-isomer. The term "threo-DOPS" used herein means DL-
threo-DOPS and L-threo-DOPS. According to pharmacological
tests, the L-isomer is about twice as effective as the
DL-isomer and it shows the same effect as the DL-isomer in
one half the amount thereof.
The pharmacological tests of threo-DOPS are illustrated
hereinafter by reference to the accompanying figures.
1. Effect of DL-threo-DOP~ on the adrenerqic activity
of patients with FAP
(1) Intravenous drip infusion test of DL-threo-DOPS
The test was carried out by administering 200 mg of DL-
threo-DOPS in 400 ml of isotonic sodium chloride solution
over 2 hours to four persons (2 normal persons and 2 FAP
patients) by intravenus drip infusion (1.7 mg/min.).
Changes in pulse rate and blood pressure were determined.
The results are shown in Figure 1.
In the graphs A to D of Figure 1, the abscissa axes
indicate time (min.) and the ordinate axes indicate changes
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in pulse rate, maximum blood pressure (mmHg) and minimum
blood pressure (mmHg), and the drip infusion rate of the
DL-threo-DOPS (mg/min.), respectively. In the graphs A to
C, the symbol o indicates normal subjects (2 persons) and
, FAP patients (2 persons).
As shown in Figure 1, the administration of DL-threo-
DOPS changed neither pulse rate nor blood pressure in the
two normal persons, whereas a sensitive hypertensive
response was observed in the two FAP patients. Further,
the time course of the response was gradual and sustained.
These properties are rarely observèd in conventional hyper-
tensors and are characteristic of threo-DOPS.
(2) Oral administration test of DL-threo-DOPS
The test was carried out by administering orally 600
mg of DL-threo-DOPS to~nine persons (4-normal persons and
5 FAP patients). Plasma norepinephrine levels and blood
pressures were determined. The results obtained from the
FAP patients are shown in Figure 2.
In the graphs A to C of Figure 2, the abscissa axes
indicate time (hrs.) and the ordinate axes indicate plasma
norepinephrine levels (pg/ml), changes in maximum blood
pressure (mmHg) and minimum blood pressure (mmHg),
respectively. The results are expressed as mean + S.E.
As shown in Figure 2, gràdual and sustained hyper-
tensive action, which reaches a peak 5 hours after oral
administration of the DL-threo-DOPS, was observed in the
patients with FAP, whereas no significant change in blood
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pressure was observed in the normal subjects. Changes in
the plasma norepinephrine level were almost parallel with
those of blood pressure and were restored to the normal
level 5 hours after the oral administration of the
DL-threo-DOPS.
The results mean that DL-threo-DOPS administered
orally is absorbed in the intestine and is converted to
(-) norepinephrine by aromatic L-amino acid decarboxylase,
which is distributed in various organs as well as nerves,
and then the norepinephrine thus formed elicits a hyper-
tensive action.
(3) Long term oral administration of DL-threo-DOPS
A clinical trial was carried out according to a simple
blind test procedure. DL-threo-DOPS was orally adminis-
tered to six FAP patients for 4 weeks (at a daily dosage
of 1.2 g, twice per day at 8 a.m. and 8 p.m.). The
patients refrained from taking any drugs for one week
before administration of the DL-threo-DOPS. After an
administration period of 4 weeks of DL-threo-DOPS, the
patients were given placebos containing lactose. In order
to estimate the clinical effect of the DL-threo-DOPS,
change in symptoms were recorded on a chart by the
patients themselves, and blood pressure in the supine
position was measured at 7 a.m., 11 a.m., 1 p.m., 4 p.m.
and 8 p.m. during the test period. The results for one
FAP patient are shown in Figure 3.
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In the graphs A to F of Figure 3, the abscissa axes
indicate time (weeks) and the ordinate axes indicate
maximum blood pressures (mmHg) measured at 7 a.m., 11
a.m., 1 p.m., 4 p.m. and 8 p.m. and dosage of DL-threo-
DOPS (g/day), respectively. The results are expressed as
mean + S. E. -
During the administration period of the DL-threo-DOPS,
significant elevations of blood pressure were observed at
11 a.m. and 1 p.m. (corresponding to 3 and 5 hours after
administration of the DL-threo-DOPS, respectively) in the
three patients suffering from orthostatic hypotension.
Dizziness and giddiness caused by orthostatic hypotension
were mitigated and activity of daily living was restored.
No side effects were observed.
2. Effect of DL-threo-DOPS on blood pressure in
patients sufferin~ from various kinds of orthostatic
hYpotension
Under the same condition as in FAP, DL-threo-DOPS was
administered intravenously to patients suffering from
familial diabetes mellitus, aortitis syndrome, idiopathic
orthostatic hypotension, acute pan-dysautonomia and ectopic
pineal tumor, respectively. Changes in pulse rate and
blood pressure were determined. The results are shown in
Figures 4 to 8.
In the graphs A to D of Figures 4, 5, 6, 7 and 8,
the abscissa axes indicate time (min.) and the ordinate
axes indicate change in pulse rate, maximum blood pressure
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(mmHg) and minimum blood pressure (mmHg), and the drip
infusion rate of the DL-threo-DOPS (mg/min.), respectively.
The results are explained in detail below.
(1) Diabetes mellitus observed in siblings (Figure 4)
Patient A: woman, 50 years old (asymptomatic ortho-
static hypotension was observed). Patient B: man, 46
years old (no orthostatic hypotension was observed). of
patients A and B, patient A showed pressor response. In
the graphs A to C of Figure 4, the symbol indicates the
patient A and o, the patient B.
(2) Aortitis syndrome (Figure 5)
Patient: woman, 65 years old. Pressor response was
observed.
(3) Idiopathic orthostatic hypotelsion (Figure 6)
Patient: man, 68 years old. Pressor response was
observed.
(4) Acute pan-dysautonomia (Figure 7)
Patient: man, 25 years old. Pressor response was
observed.
2a (5) Ectopic pineal tumor (Figure 8)
Patient: man, 24 years old. Pressor response was not
observed.
As is shown in the above~results (1) to (5), DL-threo-
DOPS induced pressor response in cases (1) to (4), but not
in case (5). This means that DL-threo-DOPS has a selective
effect on "peripheral" type orthostatic hypotension. It is
supposed that this phenomenon is due to denervation super-
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sensitivity o~ adrenergic receptors in sympathetic nervous
system.
Threo-DOPS used in the present invention is already
known and can be prepared according to a known method
such as, for example, that described in Japanese Patent
Publication (unexamined) No. 19931/1979 or Japanese Patent
Application No. 106483/1979.
A pharmaceutically acceptable acid addition salt of
threo-DOPs can be also used in the present invention.
Examples of the acid addition salts are those formed with
an inorganic acid e.g., hydrochloric acid, hydrobromic
acid, sulfuric acid or the like, or an organic acid e.g.,
fumaric acid, citric acid, tartaric acid, succinic acid or
the like.
The pharmaceutical-composition of the present invention
contain as an active ingredient threo-DOPS, or a pharma-
ceutically acceptable acid addition salt thereof, in an
amount effective for treating peripheral orthostatic hypo-
tension, and a pharmaceutically acceptable carrier or
diluent e.g. starch, lactose, dextrin, talc, magnesium
stearate, calcium carboxymethyl cellulose, finely crys-
talline cellulose or the like.
The pharmaceutical composition of the present
invention can be prepared in`a conventional dosage form
for oral administration e.g., a tablet, capsule, syrup,
liquid suspension or the like. The composition can be
also prepared in an injectable liquid dosage form e.g.,
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a solution, emulsion, liquid suspension or the like. The
composition can further contain other additives e.g. an
excipient (e.g. glucose, gelatin, etc), binder (e.g.
hydroxypropyl cellulose, polyvinyl alcohol, etc.) stabi-
lizer (e.g. ascorbic acid, sodium bisulfite, etc.) and the
like. Further, in case of an injectable dosage form, it
can contain a buffering agent (e.g. citric acid, sodium
citrate, glycine, etc.), a solubilizer ~e.g. propylene
glycol, polysorbate 80, lecithin, etc.), an agent to make
the solution isotonic (e.g. sodium chloride, boric acid,
etc.) and the like.
The pharmaceutical composition of the present
invention can be prepared, for example, by mixing,
granulating and compressing or dissolving the active
ingredient together with other ingredients as required
for the desired form of composition. The composition
is preferably in dosage unit form and each dosage unit
preferably contains the active ingredient in an amount
of from about 50 mg to about 500 mg.
In accordance with the method for treating peripheral
orthostatic hypotension of the present invention, the
active compound, threo-DOPS or a pharmaceutically accept-
able acid addition salt thereof, can be administered orally
or pareterally to the subject being treated in an effective
amount for the particular treatment. The required dosage
will vary with the dosage form, the particular condition
being treated and the severity of the condition. For
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example, in the case of oral administration, the active
compound will usually be administered to an adult in a
daily dosage of from about 0.1 g to about 6 g. In the
case of intravenous injection, the compound will usually be
administered to an adult in the daily dosage of from about
0.1 g to about 5 g. The compound will be administered one
to several times per day.
The toxicity of threo-DOPS is extremely low. The
LD50 value in mice is more than 10 g/kg (p.o.) and about
10 g/kg (i.p.). Therefore, it is believed that no harmful
effects will be produced if the compound is administered
in the above described effective amounts and, in fact, no
side effect has been observed clinically.
The following Example illustrates a process for
preparing a pharmaceutical composition of the present
invention but is not to be construed to limit the scope
thereof.
Example
2000 g of threo-DOPS, 830 g of lactose, 150 g of
calcium carboxymethyl cellulose and 20 g of magnesium
stearate were weighed and mixed together in a V-shaped
blender for about 30 minutes and then pulverized in a
hammer mill.
The powder thus obtained was filled in hard capsules
to obtain a hard capsule containing about 300 mg of threo-
DOPS per capsule.
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